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T Sheridan

Publications and source records attributed to T Sheridan.

8 recordsLinked to original sources
PubMed2000

Effects of hypokalemia on cardiac growth.

In neonatal myocytes grown in culture, reductions in extracellular potassium concentration produced a hypertrophic response as assessed by induction of early response genes, atrial natriuretic peptide and skeletal actin, and repression of the alpha3 isoform of the sodium pump in a dose dependent manner. The degree of alpha3 repression appeared to be dose dependent with decreases in media (K). Similarly, decreases in media potassium concentrations caused increases in cytosolic calcium concentration in a dose dependent manner; moreover these increases in cytosolic calcium concentration correlated quite well with repression of alpha3 expression. In contrast, although moderate reductions of potassium concentration induced upregulation of skACT and ANP, severely reduced potassium concentrations caused repression of skACT and ANP expression. In parallel studies performed in vivo, 3-5 weeks dietary K restriction induced molecular phenotypical changes similar to that seen in the neonatal myocyte model without demonstrable growth as assessed by the heart weight/body weight ratio. However, when rates subjected to dietary K restriction were subsequently subjected to acute aortic constriction, cardiac growth was greater than in rats fed a control diet. These data suggest that hypokalemia may produce molecular phenotypic alterations consistent with cardiac hypertrophy as well as contribute to hypertrophy in an in vivo model.

Animals↗
PubMed2000

Granulocyte-colony stimulating factor impedes recovery from damage caused by cytotoxic agents through increased differentiation at the expense of self-renewal.

G-CSF is routinely used to hasten recovery from chemotherapy-induced neutropenia. We have recently shown that G-CSF, when combined with stem cell-damaging cytotoxic agents, results in enhanced stem cell damage and loss of marrow reserve. To investigate the mechanisms of stem cell damage caused by G-CSF, we gave C57BL/6 (B6) mice repeated doses of cyclophosphamide ([CY] 84 mg/kg) or carmustine ([BCNU] 13.2 mg/kg) and G-CSF (250 microg/kg/day) for either four days or eight days. Two different regimens of G-CSF were chosen to study the influence of increased proliferation on hematopoiesis which was measured at the end of the first, third and sixth 14-day cycle of each cytotoxic agent and 7 and 20 weeks after completion of all cycles. A spectrum of hematopoietic indices was measured including WBC, bone marrow cellularity, granulocyte/macrophage-colony-forming cells (GM-CFC), colony-forming cells with high proliferative-potential (HPP-CFC), cobblestone area-forming cells ([CAFC]-day 7 and CAFC-day 28), and long-term marrow repopulating ability in vivo. Despite the absence of differences in peripheral blood cell counts or bone marrow cellularity 14 days after each dose, progenitor cell levels (HPP-CFC, GM-CFC, and CAFC-7) were increased up to 2.5-fold with cytotoxic agent and G-CSF administration compared with cytotoxic agent administration alone. Mice given G-CSF for eight days had the greatest number of progenitors suggesting a dose-response relationship for G-CSF administration. G-CSF resulted in a decrease in hematopoietic stem cell (CAFC-28) content when measured two weeks after each cycle of saline, CY, and BCNU. Twenty weeks after six cycles of BCNU, the reduction in stem cell levels persisted and was further decreased when G-CSF was added to BCNU for four or eight days. Data from this study suggest that the most likely explanation for the damaging effects of G-CSF is that G-CSF directly or indirectly induces stem cells to differentiate into more committed hematopoietic cells resulting in a loss of marrow reserve. This effect is enhanced in animals with an already compromised hematopoietic stem cell compartment as seen with repeated doses of BCNU.

Animals↗
PubMed2000

Reduction of marrow hematopoietic progenitor and stem cell content is not sufficient for enhanced syngeneic engraftment.

The mechanisms regulating long-term engraftment of primitive stem cells are largely unknown. Most conditioning strategies use myeloablative agents for experimental or clinical hematopoietic stem cell transplantation. Host conditioning regimens, in part, have been designed on the assumption that transplanted cells home to specific marrow sites and if these sites are occupied by host stem cells, engraftment will not take place. However, there is now evidence that stable long-term syngeneic engraftment may occur in the absence of host marrow stem cell depletion. To further study the association of engraftment with stem cell depletion, we investigated whether the marked egress of hematopoietic progenitor and stem cells from the marrow into the peripheral blood in C57BL6 mice following a single dose of cyclophosphamide (day 1) and four days of G-CSF (days 3-6) afforded an increased opportunity for long-term syngeneic donor engraftment. During and after mobilization, glucose phosphate isomerase (GPI)-1(b) mice received 30 x 10(6) GPI-1(a) marrow cells without further myeloablation. The level of donor/recipient chimerism was assessed in cell lysates after six months. Increased long-term syngeneic donor engraftment was observed prior to mobilization (before day 6), during a period of active hematopoietic regeneration following the administration of cyclophosphamide. Hematopoietic regeneration was evidenced by a reduced but rapidly increasing marrow cellularity and an increased proportion of hematopoietic progenitors in S-phase. In contrast, long-term syngeneic donor engraftment was not increased over controls during the period of maximum progenitor and stem cell mobilization (after day 5). At this time there were minimal numbers of progenitor and stem cells in the marrow. These data suggest that in the absence of host stem cell ablation, maximal engraftment does not occur during marrow progenitor or stem cell depletion, suggesting that the presence of "open" marrow sites is not a prerequisite for engraftment. The mechanisms for increased engraftment during progenitor cell regeneration following cyclophosphamide need further investigation. Understanding the mechanisms for engraftment without host stem cell ablation may allow strategies for improved long-term engraftment of syngeneic or autologous stem cells with reduced post-transplant toxicity.

Animals↗
PubMed1998

Granulocyte colony-stimulating factor enhances bone marrow stem cell damage caused by repeated administration of cytotoxic agents.

Despite the increasing use of cytokines to circumvent the acute dose-limiting myelotoxicity of cancer treatment, little is known about the combined effects of cytotoxic agents and cytokines on the primitive stem cells responsible for long-term hematopoiesis. In an experimental model, we administered cytotoxic agents that have variable effects on primitive stem cells in C57BL/6 (B6)-mice. Mice received six every-other-week doses of cyclophosphamide (CY, 84 mg/kg), VP-16 (24 mg/kg) + cisplatinum (2.4 mg/kg), carboplatinum (50 mg/kg), chlorambucil (12 mg/kg), BCNU (13.2 mg/kg), or TBI (80 cGy). Granulocyte colony-stimulating factor (G-CSF; 250 microg/kg/day) was administered subcutaneously twice daily on days 3 to 6 after each dose of the cytotoxic agent. Comparison with animals receiving the cytotoxic agent alone was made to investigate the effects of G-CSF on long-term hematopoiesis. Hematopoiesis was measured 20 weeks after the last dose of the cytotoxic agent by assessment of peripheral blood counts, marrow cellularity, progenitor cell content (colony-forming units-spleen; CFU-S), and primitive stem cell number (long-term repopulating ability and day 28 and day 35 cobblestone area-forming cell [CAFC] frequencies). Exposure to cytotoxic agents alone resulted in a significant decrease in primitive stem cells (as measured by repopulating units [RU] and day 28 and day 35 CAFC content) in animals given carboplatinum, chlorambucil, BCNU, and TBI, but not in animals treated with cyclophosphamide or VP-16 and cisplatinum. The addition of G-CSF resulted in a significant decrease in stem cell content when compared with no G-CSF administration in animals treated with chlorambucil, BCNU, or TBI. Thus, G-CSF administered after repeated exposure to cytotoxic agents, appeared to damage the primitive stem cell compartment when used in combination with agents known to damage primitive stem cells. These results, although obtained in an experimental model, should raise concerns for the indiscriminate use of G-CSF in the clinic.

Animals↗
PubMedDate not supplied

Reducing the frequency of errors in medicine using information technology.

BACKGROUND: Increasing data suggest that error in medicine is frequent and results in substantial harm. The recent Institute of Medicine report (LT Kohn, JM Corrigan, MS Donaldson, eds: To Err Is Human: Building a Safer Health System. Washington, DC: National Academy Press, 1999) described the magnitude of the problem, and the public interest in this issue, which was already large, has grown. GOAL: The goal of this white paper is to describe how the frequency and consequences of errors in medical care can be reduced (although in some instances they are potentiated) by the use of information technology in the provision of care, and to make general and specific recommendations regarding error reduction through the use of information technology. RESULTS: General recommendations are to implement clinical decision support judiciously; to consider consequent actions when designing systems; to test existing systems to ensure they actually catch errors that injure patients; to promote adoption of standards for data and systems; to develop systems that communicate with each other; to use systems in new ways; to measure and prevent adverse consequences; to make existing quality structures meaningful; and to improve regulation and remove disincentives for vendors to provide clinical decision support. Specific recommendations are to implement provider order entry systems, especially computerized prescribing; to implement bar-coding for medications, blood, devices, and patients; and to utilize modern electronic systems to communicate key pieces of asynchronous data such as markedly abnormal laboratory values. CONCLUSIONS: Appropriate increases in the use of information technology in health care- especially the introduction of clinical decision support and better linkages in and among systems, resulting in process simplification-could result in substantial improvement in patient safety.

Decision Support Systems, Clinical↗
PubMedDate not supplied

Tumor markers in the detection of recurrent transitional cell carcinoma of the bladder: a brief review.

OBJECTIVE: To determine the status of the most promising tumor markers of bladder cancer, including comparison with cytology, technical complexity and utility in patient management. STUDY DESIGN: An extensive literature search was performed, and multiple markers were evaluated. The markers with the greatest potential for use as an adjunct to cytology were reviewed to determine the value of clinical implementation. Markers with a paucity of clinical research and poor results in clinical trials were omitted from review, as were genetic and cytologic prognostic determinants. RESULTS: NMP22, bladder tumor antigen, fibrin/fibrinogen degradation products, telomerase and QUANTICYT image analysis cytometry produced the most favorable and reproducible results. Each test obtained favorable sensitivities in comparison with cytology, especially in the detection of low grade lesions. Many also retrospectively placed patients in high- and low-risk groups based on the test results, allowing increased follow-up time between cystoscopies. However, inability to detect some high grade lesions reduces their utility. CONCLUSION: Continued clinical trials using these and other predictors of bladder cancer will eventually find a test that is suitable, in sensitivity and specificity, for use in urology clinics. Until that time, these tests may be useful in conjunction with cytology to prolong the interval between cystoscopies.

Biomarkers, Tumor↗